Stroke occurs in 600,000 U.S. citizens every year and is the leading cause of neurologic disability worldwide. Most stroke victims are left with permanent sensorimotor deficits as the result of ischemia-induced brain damage. Physical therapy (PT) remains the primary strategy to improve recovery, but there is a clear need to improve rehabilitation strategies. Promising investigational studies indicate that the stimulant drug amphetamine (AMPH) can enhance the rate and extent of sensorimotor recovery when paired with PT (AMPH/PT). However, AMPH adjunct therapy remains investigational due to concerns over its side effect profile and addiction potential. Alternatives are not available because there is little understanding of the mechanism underlying the clinical benefits of AMPH. The objective of this application is to understand the pharmacology and neurobiological mechanisms underlying AMPH enhancement of PT-aided sensorirnotor recovery following stroke. Our preliminary data indicate that AMPH/PT following brain damage leads to improved motor recovery that is associated with enhanced neurite outgrowth from corticomotor cells. We also demonstrate that AMPH activates cAMP response element binding protein (CREB), a transcription factor involved in neural plasticity and neurite outgrowth via growth factor activation. We will test the hypothesis that AMPH enhances sensorimotor recovery through specific receptor activation that leads to neurite outgrowth and formation of new motor pathways. Aims I and I! will focus on the pharmacology of AMPH. In Aim I we will establish the role of noradrenergic alphal and dopaminergic D1 and D2 receptors in mediating AMPH-enhanced sensorimotor recovery in rats that have received permanent middle cerebral artery occlusion. Motor recovery will be assessed using a battery of sensorimotor tasks. In Aim II we will ascertain whether selective stimulation of alphal, D1 or D2 receptors can emulate AMPH enhancement of sensorimotor recovery. Aim III will establish that recovery of function is associated with neurite outgrowth and determine the origin of this new growth. Aim IV will focus on key signaling molecules modulated by AMPH and which are critical mediators of neuronal plasticity. First, we will determine that drug-enhanced motor recovery is associated with activation of CREB in corticomotor cells. Next we will establish a role for basic fibroblast growth factor in mediating AMPH enhanced recovery of function as well as neurite outgrowth. From Aims I and II we will identify potential drug candidates that can rapidly translate into clinical use. From Aims III and IV we will identify potential targets for future therapy. Together our findings will lead to optimization of pharmacological approaches to enhance functional recovery after stroke.